July 11, 1996

BETHESDA, Md. - What's so good about finding a disease gene? For starters, it gives scientists information about what the altered gene looks like - how its DNA structure is different from the normally functioning version. But to completely understand how an altered, or mutated, gene causes disease, scientists must learn what instructions the gene carries and what those instructions tell a cell, or trillions of them, to do. For the complex, childhood neurologic disorder ataxia-telangiectasia (A-T), a mutation in a single gene causes health problems not just in one organ but throughout the body. Furthermore, evidence suggests that otherwise healthy "carriers" of the A-T gene, who may make up 1 percent of the general population, may be at higher-than-average risk for a wide range of cancers. A major stumbling block to understanding A-T has been figuring out how one gene can influence such a wide range of biological functions literally from head to toe.

Now, an article in the July 12 issue of the journal Cell gives scientists a leg up in understanding the baffling complexities of A-T. Researchers at the National Human Genome Research Institute(NHGRI) and their collaborators report the development of a laboratory mouse with virtually all the characteristics of people with A-T, including neurologic problems, cancers of the immune system, slow growth, radiation sensitivity, and abnormal development of sperm and eggs. Although scientists have gleaned clues about the function of the human A-T gene from similar genes in single-celled yeast, the new mouse model gives them the first opportunity to study the disease in a controlled way in multi-celled animals other than humans.

"For a disease such as A-T, which affects multiple organ systems, having a mutant mouse allows us to study the role of this gene in any mammalian tissue, such as the brain, immune system and gonads," NHGRI's Carrolee Barlow, M.D., Ph.D, first author of the paper said. "Since the mice have so many problems, they may also provide an important model for studying other human diseases such as neurodegenerative disease, cancer and infertility," Barlow explained.

The development of a mouse model so quickly after the discovery of the human A-T gene only a year ago also highlights how rapidly genetics research is moving to translate gene discoveries into knowledge about how genes work and how changes in them cause disease. "For families with A-T children, the making of an animal model for this brutal disease is wonderful news," said Brad Margus, president of the A-T Children's Project and also the father of two young boys who have A-T. "We're gratified that these mice are showing so many of the symptoms that are seen in children with the disease," Margus continued.

A-T affects between 1 in 40,000 and 1 in 100,000 individuals worldwide. Some 500 children in the United States have A-T, although many more are probably undiagnosed. The first sign of the disease, a neurological symptom called ataxia, stems from loss of cells in the brain. Toddlers with A-T first exhibit an unsteady gait, slurred speech, and eventually become unable to walk and control eye movements. They are also strikingly predisposed to leukemia and lymphoma and are profoundly sensitive to radiation exposure. Most children with A-T develop characteristic telangiectases - dilated blood vessels on the surfaces of their eyes and facial skin, and many A-T patients have weakened immune systems, leading to recurrent respiratory infections. People with A-T usually die in their teens or early 20s.

In part because the symptoms of A-T are so diverse, scientists thought for over a decade that several genes caused the disease. But discovery last year of the human A-T gene, called ATM, by a team led by Yossi Shiloh at Tel Aviv University indicated alterations in a single gene are responsible for A-T's range of health problems.

Studies since then have shown that the normal ATM gene encodes a protein that appears to play a role in transferring signals that control the rate of cell division. The ATM protein also helps ensure that any damaged DNA is caught and repaired before cells divide, so the harm is not passed on to a cell's descendants.

In the new report, researchers focused on a gene called "Atm" on the mouse's 9th chromosome, which matches the human ATM gene located on human chromosome 11. They engineered a piece of DNA to contain a "knockout" mutation of Atm and inserted that DNA into mouse embryo cells grown in a laboratory dish.

In a few of the cells, the engineered, mutated DNA replaced the matching, normal DNA already in the cells, and by that method, the engineered mutations became part of the cells' genetic make-up.

The altered cells were then introduced into very early mouse embryos, which developed into mouse pups. When these altered mice grew, they were bred to produce offspring with a genetic profile similar to that of children with A-T. That is, the offspring carried two copies of the mutant A-T gene in their DNA.

The scientists performed several tests on the A-T mouse pups, to determine if they developed the same problems as do children with A-T. Sure enough, the young mice were smaller than normal, had movement problems, infertility, immune system deficiencies, a high likelihood of cancer and were extremely sensitive to radiation.

While most of the knowledge the "Atm" mouse model provides will be applied to understanding A-T in the 500 or so children who have the disease, still to come are studies that shed light on the health risks of an estimated 1 percent of the general population - about 2.5 million people in the United States - who carry only one copy of the ATM gene and do not have the disease. Some studies have suggested that such healthy "carriers" develop cancer about four times more frequently than do non-carriers and may be more sensitive than usual to radiation. Women carriers of a single ATM mutated gene may be at five times greater risk for breast cancer than are female non-carriers. The "Atm" mutant mice are currently being used to investigate the cancer risk in mice with one copy of the abnormal "Atm" gene.

For other disorders, when researchers have attempted to make mouse models of human genetic diseases, the mouse often has different findings than human patients. "We are tremendously excited about having a mouse that so closely mimics human A-T characteristics. These mice will allow us to study the important role that this gene plays in the normal functioning of a variety of cell types, such as neurons, the immune system and the reproductive cells," explained NHGRI senior investigator, Anthony Wynshaw-Boris, M.D., Ph.D. "But most importantly, we now have an animal in which to test potential therapies, which would be impossible in human A-T patients. We are hopeful that such therapies will ultimately help patients with this devastating disease," Wynshaw-Boris concluded.